New Gene Discovery Suggests Which Patients CTI’s Brostallicin May Benefit

April 16, 2008

By Flinn Foundation

[Source: PRNews Wire] – Systems Medicine LLC (SM), a wholly-owned subsidiary of Cell Therapeutics, Inc. (CTI) , presented data from a preclinical study identifying the genetic markers in patients more likely to respond to treatment with the experimental drug, brostallicin, at the 2008 American Association for Cancer Research (AACR) annual meeting. These findings will be used to guide future development of brostallicin by suggesting which patients are most likely to respond when treated with brostallicin, potentially making the drug’s development more efficient. This method of drug development is known as the context of vulnerability approach. The study was co-directed by Jeffrey A. Kiefer, Ph.D., and Holly Yin, Ph.D. in the Translational Genomics Research Institute’s Pharmaceutical Genomics Division located in Scottsdale, Arizona.

“This study is an example of using a pharmacogenomic screening approach to find insights that guide the selection of specific contexts of vulnerability for brostallicin. These results provide information on which genetic characteristics to look for in determining whether or not a patient might benefit from treatment with brostallicin. In SM and CTI’s continued efforts to make cancer more treatable, results like these broaden our knowledge of brostallicin’s context of vulnerability, and bring us closer to being able to offer the right drug to each patient,” said Jeffrey Jacob, CEO of SM.

In the study, the NCI-60 cell line panel was profiled for brostallicin response and correlated with specific genomic information derived from the cell line panel. The NCI-60 is a group of 59 human cancer cell lines derived from tumor tissue — brain, blood and bone marrow, breast, colon, kidney, lung, ovary, prostate, and skin. Scientists often use cell lines, also called models, in preclinical studies in a laboratory setting. The information learned from preclinical studies helps guide the design of future clinical trials. An integrative knowledge mining strategy was used to identify the genomic and functional consequences of brostallicin response. According to the study abstract, “Gene Set Enrichment Analysis (GSEA) revealed unique associations between cells’ sensitivity to brostallicin,” and distinct sets of genes, “including significant associations with particular aspects of DNA repair.” In addition to correlative genomic analyses on the NCI-60 cell line panel, a high-throughput siRNA (HT-RNAi) screen was conducted to functionally identify those gene products involved in brostallicin response. RNA interference is an experimental technique that allows for the targeted reductions of gene expression. A systematic evaluationof 7,000 genes was conducted in a cisplatin resistant variant of the ovarian cancer cell line A2780. A number of interesting ‘hits’ or targets were identified in the screen that modulate the cells sensitivity to brostallicin and represent unique and functionally based contexts of vulnerability.

Knowledge mining of the brostallicin siRNA gene hits revealed enrichment of a number of important molecular concepts and important genes involved in DNA repair. On the basis of these and related studies, a clinical trial will soon be initiated specifically targeting patients with genetic defects in mismatch repair genes such as BRCA1 and 2, which are associated with susceptibility for breast and ovarian cancer.

To review the poster and see more detailed information aboutthe study, please go to http://www.celltherapeutics.com/investors_news-updates.html